1. Academic Validation
  2. Novel Triapine Derivative Induces Copper-Dependent Cell Death in Hematopoietic Cancers

Novel Triapine Derivative Induces Copper-Dependent Cell Death in Hematopoietic Cancers

  • J Med Chem. 2019 Mar 28;62(6):3107-3121. doi: 10.1021/acs.jmedchem.8b01996.
Ge Chen 1 2 Chunyi Niu Jianhua Yi Lin Sun Hengyi Cao 2 Yanjia Fang Taijie Jin 2 Ying Li Chunli Lou Jingwu Kang Wanguo Wei 3 Jidong Zhu
Affiliations

Affiliations

  • 1 CAS Center for Excellence in Molecular Cell Science , Shanghai Institutes of Biochemistry and Cell Biology, Chinese Academy of Sciences , Shanghai 200031 , China.
  • 2 University of Chinese Academy of Sciences , Beijing 100049 , China.
  • 3 Shanghai Advanced Research Institute , Chinese Academy of Sciences , Shanghai 201210 , China.
Abstract

Triapine, an iron chelator that inhibits ribonucleotide reductase, has been evaluated in clinical trials for Cancer treatment. Triapine in combination with Other chemotherapeutic agents shows promising efficacy in certain hematologic malignancies; however, it is less effective against many advanced solid tumors, probably due to the unsatisfactory potency and pharmacokinetic properties. In this report, we developed a triapine derivative IC25 (10) with potent antitumor activity. 10 Preferentially inhibited the proliferation of hematopoietic cancers by inducing mitochondria Reactive Oxygen Species production and mitochondrial dysfunction. Unlike triapine, 10 executed cytotoxic action in a copper-dependent manner. 10-Induced up-expression of thioredoxin-interacting protein resulted in decreased thioredoxin activity to permit c-Jun N-terminal kinase and p38 activation and ultimately led to the execution of the cell death program. Remarkedly, 10 showed good bioavailability and inhibited tumor growth in mouse xenograft models. Taken together, our study identifies compound 10 as a copper-dependent antitumor agent, which may be applied to the treatment of hematopoietic cancers.

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